Abstract | BACKGROUND: OBJECTIVES: The goals of this study were to investigate the inhibition of late INa by eleclazine using a sample of long QT syndrome type 3 (LQT3) and overlap LQT3/ Brugada syndrome mutant channels; to compare the apparent binding rates for eleclazine with those for other class 1 antiarrhythmic agents; and to investigate the binding site. METHODS: Wild-type human cardiac voltage-gated sodium channel (hNaV1.5) and 21 previously reported variants were studied using patch clamp recordings from a heterologous expression system. RESULTS:
Eleclazine inhibited anemone toxin II-enhanced late INa from wild-type hNaV1.5 with a drug concentration that causes 50% block of 0.62 ± 0.12 μM (84-fold selectivity over peak INa). The drug concentration that causes 50% block of eleclazine to inhibit the enhanced late INa from LQT3 mutant channels ranged from 0.33 to 1.7 μM. At predicted therapeutic concentrations, eleclazine and ranolazine inhibited peak INa to a similar degree as assessed with 4 overlap LQT3/ Brugada syndrome mutations. Eleclazine was found to interact with hNaV1.5 significantly faster than ranolazine and 6 other class 1 antiarrhythmic agents. Engineered mutations (F1760A/Y1767A) located within the local anesthetic binding site decreased the inhibition of late INa and peak INa by eleclazine. CONCLUSION: At predicted therapeutic concentrations, eleclazine elicits potent inhibition of late INa across a cohort of NaV1.5 mutant channels. These properties are consistent with a class 1b antiarrhythmic agent that associates with unusually rapid binding/unbinding rates.
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Authors | Nesrine El-Bizri, Cheng Xie, Lynda Liu, James Limberis, Michael Krause, Ryoko Hirakawa, Steven Nguyen, Dennis R Tabuena, Luiz Belardinelli, Kristopher M Kahlig |
Journal | Heart rhythm
(Heart Rhythm)
Vol. 15
Issue 2
Pg. 277-286
(02 2018)
ISSN: 1556-3871 [Electronic] United States |
PMID | 29017927
(Publication Type: Journal Article)
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Copyright | Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- Oxazepines
- Sodium Channel Blockers
- eleclazine
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Topics |
- Action Potentials
- Cardiac Conduction System Disease
(drug therapy, metabolism, physiopathology)
- Humans
- Long QT Syndrome
(drug therapy, metabolism, physiopathology)
- Myocytes, Cardiac
(drug effects, metabolism, pathology)
- Oxazepines
(therapeutic use)
- Patch-Clamp Techniques
- Sodium Channel Blockers
(therapeutic use)
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